Abstract C168: A two stage prospective clinical trial with irofulven treatment targeting a selected subgroup of castration- and docetaxel resistant prostate cancer patients

• Published in: Molecular cancer therapeutics Vol. 14; no. 12_Supplement_2; p. C168
• Main Authors: Knudsen, Steen, Jensen, Thomas, Hansen, Anker, Buhl, Ulla, Rasmussen, Annie, Pratt, Bruce, Asaithambi, Arun, Brünner, Nils, Jensen, Peter Buhl
• Format: Journal Article
• Language: English
• Published: 01-12-2015
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-15-C168

Abstract
Irofulven, a DNA damaging semi -synthetic analog of Illudin S (phytotoxin from Omphalotus illudins, jack-o'-lantern mushroom) which in the body is activated by prostaglandin reductase, has shown promising clinical activity in a range of cancer forms but the objective response rates were too low to justify further clinical development. Of particular interest is that irofulven may not be a substrate of the mdr-1 drug efflux pump and thereby potentially active in prostate cancer patients with acquired resistance to docetaxel. We have now developed an irofulven responsive predictor which is based on gene expression data by comparing associations between gene expression profiles and growth inhibition in a panel of cell lines treated with irofulven. A second step has included filtering the identified gene expression profile against mRNA expression from a collection of 3200 human tumors. Only genes being differentially expressed in the clinical tumor material were retained in the model. A total of 205 mRNA's were selected for the final irofulven responsive profile. The profile can be converted to a single score of predicted irofulven responsiveness. We are now initiating a prospective clinical trial (Simon's two stage design) in selected patients with castration - and docetaxel resistant prostate cancer and with a favorable irofulven responsive profile. We are screening 600 prostate cancer samples (FFPE tissue) in order to select the 10% of patients with the highest likelihood of benefit from irofulven treatment. Primary end-points are objective response rate and changes in serum PSA.
Citation Format: Steen Knudsen, Thomas Jensen, Anker Hansen, Ulla Buhl, Annie Rasmussen, Bruce Pratt, Arun Asaithambi, Nils Brünner, Peter Buhl Jensen. A two stage prospective clinical trial with irofulven treatment targeting a selected subgroup of castration- and docetaxel resistant prostate cancer patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C168.